Small cell lung cancer (SCLC) is a chemotherapy responsive disease and is associated with neuroendocrine features by both clinical and in vitro studies. Unlike SCLC, non-small cell lung cancer (NSCLC) has been only moderately responsive to chemotherapy and is associated with such features in only a minority of cases (10-20%). Patients with neuroendocrine features may behave clinically more like SCLC and thus may be more responsive to chemotherapy. A preliminary retrospective study of patients with advanced NSCLC showed that patients with neuroendocrine features (neuron-specific enolase, Leu-7 and chromogranin A) as measured by immunoperoxidase on paraffin-embedded tissue has an increased likelihood of response to chemotherapy and improved survival. If these findings are confirmed, neuroendocrine studies may help select patients who ar likely to benefit from chemotherapy. The proposed study is designed to correlate neuroendocrine features with clinical parameters of patients placed on Cancer and Leukemia Group B (CALGB) NSCLC protocols. The pathological tissue blocks will be obtained for each patient, and 4um slides will be prepared for immunoperoxidase stained for neuron-specific enolase, Leu-7, chromogranin A. We plan to investigate the prognostic significance of neuroendocrine in 3 groups of patients with NBCLC. We plan 1) to retrospectively study a group of stage IIIA and IIIB NSCLC patients treated on CALGB protocols #8433 and 8831; 2) to prospectively investigate stage IIIA (N2, positive mediastinoscopy) NSCLC patients treated on CALGB #8935 both before and after chemotherapy; and 3) to prospectively analyze neuroendocrine markers in stage II and IIIA (N2, negative mediastinoscopy) NSCLC patients treated on a surgical adjuvant study. The presence of these markers will be correlated with treatment, disease free survival, survival and patterns of relapse. Identification of a subset of patients that may be more responsive to chemotherapy has important implications. Patients unlikely to respond could be spared toxic therapy, while patients who are most likely to benefit could be selected for chemotherapy. Perhaps of more significance, these techniques may help identify patients with early stage disease who may benefit from adjuvant chemotherapy.